Cardiac surgery provokes extremes in human physiology, with patients exposed to robust stress and acute perturbations in proinflammatory and prothrombotic pathways implicated in the pathogenesis of perioperative myocardial injury (PMI). Despite advances in surgical, cardioprotective and anesthetic techniques, the incidence of PMI after cardiac surgery remains 7-15%, is consistently associated with short and long-term mortality, and is poorly predicted by clinical and procedural risk factors. A systematic strategy is proposed using microarray technology to identify candidate genes contributing to PMI in two animal models of cardiac surgery (rat and pig), and in banked tissue samples collected intraoperatively from cardiac surgical patients. The intent is to then investigate the relevance of DNA sequence variation in these candidate genes to susceptibility for PMI in a large population-based study. It is postulated that pathophysiologic processes leading to PMI in cardiac surgery are accompanied by cellular and biochemical alterations reflected by changes in gene expression patterns in susceptible tissues. It is further hypothesized that inherited DNA sequence variation in these same genes is at least in part responsible for inter-individual variation in susceptibility to PMI. The experimental design, which derives power from its comparative nature, allows differentiating between the contributing effects of the two main perturbations associated with the cardiac surgery environment: cardiopulmonary bypass (CPB) and myocardial ischemia-reperfusion (IR). Three specific aims include: 1) identifying evolutionary conserved myocardial-specific candidate genes for PMI using whole genome expression profiling across multiple species (rat, pig, human); 2) refining susceptibility determinants for PMI by comparing myocardial responses to CPB/IR in well-characterized parental and chromosomally-substituted (consomic) rat strains using whole genome expression analysis. The intersection of data from these various models enables the prioritization of candidate genes for PMI in a tissue-specific manner;and 3) testing association between polymorphisms in candidate genes identified in aims 1 and 2 and PMI using an existing biorepository from a population of 3,500 well-phenotyped cardiac surgical patients enrolled in the Perioperative Genetics and Safety and Outcomes Study (PEGASUS). This experimental approach will require coordinated efforts in cardiac surgery, anesthesiology and critical care, evolutionary biology, computational analysis, and statistical genetics and epidemiology, and the team members assembled reflect this diversity. This highly collaborative project is novel for its ability to translate unique animal model research findings to understanding the genetic architecture of myocardial susceptibility to the unique perioperative environmental stressors in the population at large, with implications in perioperative risk stratification of cardiac surgical patients and identification of novel therapeutic targets.